(1) Field of the Invention
The present invention relates to the preparation of oxazole, imidazole, and pyrazole boryl compounds, using iridium complexes. The present invention also relates to novel compounds.
(2) Description of the Related Art
Oxazoles have a wide variety of applications in synthetic organic chemistry and have been found in numerous natural products such as hennoxazole, thiangazole, calyculin, halicondrins, pyrenolide, virginiamycin, amphotericin, and phorboxazoles.a New studies have illustrated the particular utility of 5-substituted oxazoles. For example, a very recent structure-activity relationship study targeting the 5-position of an oxazole based inhibitor of fatty acid amide hydrolase (FAAH) revealed that the optimal position for substitution was the meta-position. Concurrent with these studies, a series of small, nonaromatic C5-substituents was also explored and revealed that the Ki follows a well-defined correlation with the Hammett p constant (=3.01, R2=0.91) in which electron-withdrawing substituents enhance potency, leading to inhibitors with K is as low as 400 pM (20n). Proteomic-wide screening of theses inhibitors revealed that most are exquisitely selective for FAAH over all other mammalian proteases.b In another investigation, a series of 4-(4-cycloalkyl/aryl-oxazol-5-yl)benzenesulfonamide derivatives were synthesized and evaluated for their abilities to inhibit cyclooxygenase-2 (COX-2) and cyclooxygenase-1 (COX-1) enzymes. This work led to the identification of a potent, highly selective, and orally active COX-2 inhibitor JTE-522 [4-(4-cyclohexyl-2-methyloxazol-5-yl)-2-fluorobenzenesulfonamide], which is currently in phase II clinical trials for the treatment of rheumatoid arthritis, osteoarthritis, and acute pain.c 2-Anilino-5-phenyloxazoles have also been identified as inhibitors of VEGFR2 kinase. In this case, optimization of both aryl rings led to very potent inhibitors at both the enzymatic and cellular levels. These oxazole-based compounds had excellent solubility and good oral PK when dosed as the bis-mesylate salt and demonstrated in vivo efficacy against HT29 human colon tumor xenografts. Furthermore substitution at the 5-position proved especially instructive as X-ray crystallography confirmed the proposed binding mode and revealed interesting differences in orientation of 2-pyridyl and 3-pyridyl rings, respectively, attached at the meta position of the 5-phenyl ring.d In yet another report, the antibacterial activity of a range of 5-alkyl, 5-alkenyl, and 5-heterosubstituted 2-(1-normon-2-yl) oxazoles against a range of Gram-positive and Gram-negative organisms demonstrated the importance of substitution on potency. Compounds possessing an acid functionality directly on, or close to, the ring were found to be of greatly decreased potency, while increasing lipophilicity with greater chain length led to increased potency of these derivatives.e Likewise, in the search for transthyretin (TTR) amyloid fibril inhibitors, oxazoles bearing a C(4) carboxyl group and various aryls at the C(2) position of the oxazole ring reveals that a 3,5-dichlorophenyl substituent significantly reduced amyloidogenesis. The efficacy of these inhibitors was enhanced further by installing an ethyl, a propyl, or a CF3 group at the C(5) position. The CF3 substitution at C(5) also improves the TTR binding selectivity over all the other proteins in human blood.f 